Project Summary In contrast to dramatic declines in older populations, the incidence of colorectal cancer (CRC) has nearly doubled among younger adults since the early 1990s. Mechanisms contributing to the rising incidence of young?onset CRC (age <50 years) have puzzled researchers for years, and to date, family history of polyps or CRC remains the only clearly established risk factor. Our prior work shows a strong birth cohort effect, whereby incidence increased markedly among persons born in or after the 1960s. Higher incidence of young? onset CRC among this birth cohort (approximately Generation X) implicates environmental exposures in early life. Antibiotics, cesarean delivery, birth weight, and childhood obesity ? increasingly prevalent in early life ? may contribute to rising incidence of young?onset CRC. Prevalence of these environmental exposures exploded among persons born after 1960. For example, broad?spectrum antibiotic use nearly tripled among children of the 1960s, and cesarean deliveries increased from 5% of births in 1960 to more than 30% in 2015. Mounting evidence suggests these environmental exposures alter gut microbiota, and gut microbiota may act as a key promoter of carcinogenesis, thus, mediating the relationship of environmental exposures with CRC. In the proposed project, we will generate timely evidence concerning effects of environmental exposures in early life on risk of young?onset CRC and advance our understanding of causal mechanisms contributing to this disease. We will leverage existing data on 19,044 children enrolled in the Child Health and Development Studies (CHDS), and for whom we can ascertain young?onset CRC diagnoses with high?quality cancer registry data. CHDS comprises a diverse, population?based cohort of children born in the 1960s to women receiving prenatal care in the Kaiser Foundation Health Plan (Oakland, California). CHDS collected information on prenatal visits, labor and delivery, and pediatric visits. These data do no rely on parents' or study participants' memory but excellent capture of individual?level risk factors collected prospectively from medical records. We will append these well?characterized data with information on family history and germline mutations by re? contacting CHDS participants for consent to obtain biospecimens. Our innovative use of data from an existing cohort study, combined with genomic data collected in the present day, will provide a more complete picture of young?onset CRC than has been previously possible. We will: 1) Estimate the association of antibiotics (prenatal, perinatal, childhood), cesarean delivery, birth weight, and childhood obesity and young?onset CRC; 2) Explore whether the association between these early life exposures and young?onset CRC differs among those with and without a family history and/or germline mutation; and 3) Estimate the population impact of early life exposures on risk of young?onset CRC, by synthesizing effect estimates with prevalence of early life exposures derived from population?based surveys. By leveraging data on early life exposures from CHDS, we will generate new evidence that may ultimately be applied to CRC prevention and risk?reduction strategies.